HGG Advances最新文献

{"title":"Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.","authors":"Nikki D Russell, Jonathan M Downie, Mark B Bromberg, Stefan M Pulst, Lynn B Jorde","doi":"10.1016/j.xhgg.2026.100614","DOIUrl":"10.1016/j.xhgg.2026.100614","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and whole-exome sequencing data from 1,034 individuals with ALS were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA (mtDNA) polymerase, emerged as a top candidate gene. RNA sequencing (RNA-seq) analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways, including translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected control subjects. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mtDNA maintenance. Additionally, POLG variant carriers had elevated mtDNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mtDNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to the ALS etiology.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100614"},"PeriodicalIF":3.6,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-informed CRISPR screen identifies FLNB as a congenital heart disease and ciliopathy gene.","authors":"Angelo Arrigo, Venkatramanan Rao, Aakrosh Ratan, Saurabh S Kulkarni","doi":"10.1016/j.xhgg.2026.100580","DOIUrl":"10.1016/j.xhgg.2026.100580","url":null,"abstract":"<p><p>Heterotaxy (HTX) is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart disease (CHD). Despite advances in sequencing, many CHD and HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR-Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD and HTX, 3 with recessive and 2 with damaging heterozygous variants in FLNB. Disrupting flnb in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD and HTX.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100580"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12974105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A framework for the molecular identification of CHIP for clinical research.","authors":"Philip Harraka, Robert L O'Reilly, Jared Burke, Paul Yeh, Kerryn Howlett, Kiarash Behrouzfar, Daniele Belluoccio, Amanda Rewse, Brigid M Lynch, Kristen J Bubb, Stephen J Nicholls, Roger L Milne, Melissa C Southey","doi":"10.1016/j.xhgg.2026.100575","DOIUrl":"10.1016/j.xhgg.2026.100575","url":null,"abstract":"<p><p>Clonal hematopoiesis of indeterminate potential (CHIP) is associated with many diseases of aging. Large research initiatives are needed to develop clinical guidelines for the management of individuals with CHIP and their risk of disease. However, little guidance is available for the classification of variants as CHIP associated or how to identify individuals consistently and systematically as having CHIP. This study aimed to develop and execute a resource-mindful framework for identifying individuals with CHIP, and those without, for downstream clinical studies. This framework was used to categorize CHIP in a cross-section of 2,328 participants from the Australian Breakthrough Cancer Study. DNA extracted from saliva samples was sequenced for a panel of ten gene regions that frequently carry variants that are associated with CHIP. Variants in these regions were curated for CHIP according to field-specific criteria. Individuals were categorized as either CHIP positive, CHIP negative, or CHIP indeterminate based on their variant findings. Sequencing was successfully performed on 2,328 individuals. The mean age (± standard deviation) was 68 ± 3 years, and 48% were men. 347 participants (15%) were identified as CHIP positive with a total of 400 CHIP-associated variants. 1,442 participants (62%) were considered CHIP negative based on finding no somatic variation within the target regions. The remaining 539 (23%) were considered CHIP indeterminate because they had at least one variant that could not be interpreted. This framework provides a consistent approach to the categorization of individuals as CHIP positive or CHIP negative for clinical research and provides an opportunity for improved harmonization in the curation of CHIP.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100575"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12925157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASAH2 deficiency affects sphingolipid homeostasis and neuromotor control, causing a progressive neurological disorder.","authors":"Marcello Scala, Ranjan K Sahu, Mariasavina Severino, Monica Traverso, Michele Iacomino, Marina Pedemonte, Filippo Santorelli, Stefano Tozza, Federico Zara, Chiara Fiorillo, Hyung-Lok Chung","doi":"10.1016/j.xhgg.2026.100587","DOIUrl":"10.1016/j.xhgg.2026.100587","url":null,"abstract":"<p><p>Sphingolipids are integral components of cell membranes and modulate cell survival, proliferation, and apoptosis. ASAH2 is a brain- and gut-enriched gene encoding the neutral N-acylsphingosine amidohydrolase 2, a poorly characterized member of the human ceramidase family. This enzyme plays a pivotal role in maintaining the sphingolipid homeostasis, which is crucial for neurogenesis and synaptic function in the central and peripheral nervous systems. In fact, a dysregulated sphingolipid metabolism is associated with progressive neurological conditions, including Alzheimer disease and Parkinson disease. Here, we report the identification of biallelic ASAH2 variants in an individual with a neurodevelopmental condition featuring cognitive impairment, neuropathy, ophthalmoplegia, and progressive cerebellar and extraocular muscles atrophy. Through exome sequencing, we identified very rare missense ASAH2 variants, predicted to be deleterious by in silico analyses. Muscle biopsy histopathologic evaluation revealed features suggestive of neuropathic damage. Lipidomic profiling revealed a hyper-accumulation of glucosylceramide in the subject's cells. Then, the functional investigation of the ASAH2 variants in Drosophila showed the production of an unstable protein and consistent loss-of-function neuromotor phenotypes. Our findings support ASAH2 as a candidate gene for a previously uncharacterized neurodevelopmental disorder with neuropathic features and progressive cerebellar atrophy, underscoring the important role of this ceramidase in human nervous systems.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100587"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EEFSEC deficiency underlies a human selenopathy with primary neurodevelopmental origins via midbrain-hindbrain hypoplasia.","authors":"Zhiyi Xia, Hui Liu, Pengbo Guo, Chongfen Chen, Lili Ge, Longfei Tang, Yaodong Zhang, Yanli Ma","doi":"10.1016/j.xhgg.2026.100563","DOIUrl":"10.1016/j.xhgg.2026.100563","url":null,"abstract":"<p><p>Bi-allelic mutations in EEFSEC, a key factor in selenoprotein synthesis, cause a severe human selenopathy characterized by developmental delay, spasticity, and profound cerebellar atrophy. While previous studies in invertebrate models framed this condition as an early-onset neurodegenerative disorder, the contribution of primary developmental defects to the severe brain malformations in patients has remained a critical unanswered question. Here, we address this gap using a zebrafish model of EEFSEC deficiency. We discovered that loss of eefsec function does not impair global somatic growth but instead causes specific and significant hypoplasia of the midbrain and hindbrain-the embryonic precursors to the human cerebellum and brain stem. These structural defects directly correlate with robust behavioral impairments, including diminished locomotion and blunted escape responses, mirroring the severe motor dysfunction in patients. Critically, our findings provide the in vivo evidence from a vertebrate model that this disorder involves a primary neurodevelopmental defect, which underlies the severe brain malformations and creates a structurally vulnerable nervous system. This establishes a developmental basis for understanding this condition. We propose that this initial failure in brain construction, which we term a developmental selenopathy, creates a structurally vulnerable nervous system, providing a plausible mechanistic explanation for the human phenotype and proposing a framework for understanding this devastating condition.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100563"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scaling genomic reanalysis to unlock diagnoses and transform rare disease care.","authors":"Shira Rockowitz, Wanqing Shao, Courtney French, Tina K Truong, Jacob Hagen, Rylee McGonigle, Alexa Geltzeiler, Beth Sheidley, Lacey Smith, Alissa M D'Gama, Mira Irons, Janet Chou, Joan Stoler, Amy Kritzer, Lance Rodan, Akiko Shimamura, Olaf Bodamer, Stephanie Sacharow, Janet S Soul, Siddharth Srivastava, Amy Roberts Kennedy, Aya Abu-El-Haija, Abbe Lai, Heather Olson, Jane Juusola, Erin Ryan, Bethany Friedman, Anupama Singh, Cliff Li, Rittika Mallik, Gwendolyn Strickland, Gillian Prinzing, Alisa Mo, Anne O'Donnell-Luria, Jeff Bolton, Philip M Boone, William Brucker, Michael Duyzend, Sonal Mahida, David T Miller, Jacklyn Omorodion, Jeanette Petit, Jonathan Picker, Annapurna Poduri, Colleen Carlston, Monica H Wojcik, Piotr Sliz, Wendy K Chung","doi":"10.1016/j.xhgg.2026.100582","DOIUrl":"10.1016/j.xhgg.2026.100582","url":null,"abstract":"<p><p>Genomic reanalysis can identify causative variants for rare diseases as patient phenotypes evolve and gene-disease knowledge expands. Despite its diagnostic value, routine reanalysis is limited by clinician capacity, lack of patient follow-up, data silos, cost, and lack of availability of clinical data to testing laboratories that are not obligated to conduct reanalysis. The Children's Rare Disease Collaborative at Boston Children's Hospital (BCH) has integrated genomic and phenotypic data from over 15,500 patients into a clinician-facing platform. Leveraging this infrastructure, we developed a Proactive Genomic Reanalysis (PGR) workflow at BCH for clinical sequencing data that is centralized, semi-automated, and clinically integrated. Here, we report initial results and outline required resources and transferable insights applicable to other healthcare settings. Initial pilot implementation, applied to a subset of clinical sequencing patients' data, revealed practical challenges, notably clinician turnover and patient recontact difficulties. Of 42 patients' candidate variants discovered by the PGR bioinformatics pipeline and returned to treating clinicians, 33 were determined to have a high suspicion of disease causality and an additional 3 were determined to be candidate variant of uncertain significance. A process to generate reports and return results to patients was initiated when applicable. Although the initial pilot implementation was limited, the PGR bioinformatics pipeline is designed to be utilized iteratively, making reanalysis a continuing process. This work highlights the feasibility and impact of centralized PGR processes and the potential for healthcare institutions to scale genomic reanalysis.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100582"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12993396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of alternative splicing in WFS1 associated with low-frequency hearing loss in the common marmoset.","authors":"Shu Yokota, Hidekane Yoshimura, Shin-Ya Nishio, Erika Sasaki, Keisuke Mukasa, Shin-Ichi Usami, Yutaka Takumi","doi":"10.1016/j.xhgg.2026.100578","DOIUrl":"10.1016/j.xhgg.2026.100578","url":null,"abstract":"<p><p>Approximately 200 genes have been identified as causative in hereditary hearing loss. Genetic testing is increasingly important, not only for accurate diagnosis but also for predicting audiometric profiles, prognoses, and potential syndromic features. Hereditary hearing loss can be syndromic or nonsyndromic, with nonsyndromic forms further classified by inheritance: autosomal-dominant or autosomal-recessive. In autosomal-dominant cases, three pathological mechanisms-haploinsufficiency, dominant-negative effects, and gain of function-are often implicated. Moreover, specific genes correlate with distinct audiometric patterns: WFS1 variants typically cause low-frequency hearing loss, whereas KCNQ4 and POU4F3 variants are linked to high-frequency loss. To investigate the underlying mechanisms of these frequency-dependent patterns, gene expression across cochlear turns was compared in mice, but interpretations of the results were limited because of inherent structural differences between rodent and primate cochleae. Therefore, the common marmoset (Callithrix jacchus), which offers closer anatomical and functional similarity to human cochleae, was utilized herein as an improved model. Using RNA sequencing (RNA-seq) across cochlear turns of common marmosets, the present study aimed to uncover gene expression and alternative splicing patterns that may explain tonotopic manifestations in hereditary hearing loss, including those caused by WFS1 variants, the present study being one such using common marmoset cochlear RNA-seq data, and these findings are highly valuable for genetic diagnosis and the development of gene therapies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100578"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12936726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-specific pathogenicity predictor for chromatin remodeling BAF complex-associated neurodevelopmental disorders.","authors":"Joshua Hack, Mohammad Nazim","doi":"10.1016/j.xhgg.2026.100583","DOIUrl":"10.1016/j.xhgg.2026.100583","url":null,"abstract":"<p><p>Advancements in whole-genome sequencing have increased the number of variants of uncertain significance (VUS) identified in human genomes. This has created a diagnostic bottleneck for genetic counselors tasked with sifting through these variants and determining those most likely to be causative for a patient's clinical presentation. Machine learning (ML) tools can aid in identifying pathogenic variants from VUS, but there is a need for gene-specific algorithms that predict pathogenic variants with high accuracy. To address this need, we present a workflow for developing gene-specific, ensemble-learning ML tools, that leverage outputs from other algorithms, locations of variants within the gene, and evolutionary conservation data to make a prediction of pathogenicity. Variants in SMARCA2 and SMARCA4 that are associated with rare neurodevelopmental diseases were used to screen 15 ML algorithms. A random forest learner was tuned to yield a final accuracy of 0.93 on holdout data. Generalizing this predictor to other BRG1/BRM-associated factor (BAF) complex proteins resulted in a sharp decline in performance. We trained a final predictor for all genes in the study to create a predictor that identifies pathogenic variants in these BAF subunits with an accuracy of 0.91 on holdout data. This predictor specific to BAF complex proteins performs with higher accuracy and area under the precision-recall curve than any other predictor. The decline in performance when generalized to other proteins emphasizes the need for the gene-specific calibration of predictors. Our workflow for the development of such models provides a quick, computationally inexpensive route for improving the ML tools available to genetic counselors.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100583"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147322285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking barriers to completing genetic testing for inherited breast cancer among at-risk Black women using a community-based participatory research approach.","authors":"Sarah H Choi, Sanjana Ramesh, Shanequa Reed, Georgina Menyah, Pamela Ganschow, Vida Henderson, Henry M Dunnenberger","doi":"10.1016/j.xhgg.2026.100591","DOIUrl":"10.1016/j.xhgg.2026.100591","url":null,"abstract":"<p><p>National guidelines from the US Preventive Services Task Force and the National Comprehensive Cancer Network recommend the use of family-health-history (FHH)-based risk assessment tools to guide genetic testing (GT) among women with an increased risk of inherited cancer and inform personalized cancer risk management. Prior research has focused on attitudes toward and decisions about initial uptake of GT in Black patients but little is known about the factors that impact the subsequent completion of GT after they have already provided consent. Using a community-based participatory research (CBPR) approach, we aimed to identify barriers and actionable strategies to improve GT completion offered through the Breast Health Assessment (BHA), an FHH screening tool administered at routine mammography visits. We conducted semi-structured interviews with 12 Black women who screened high-risk for inherited breast cancer and consented to GT through the BHA, but did not complete saliva sample collection. Thematic analysis revealed that lack of dedicated support throughout the BHA workflow emerged as a key obstacle to sample collection, whereas medical mistrust, shame, and limited knowledge were largely regarded as cultural barriers that had no impact on GT completion. Low utilization among participants reflected logistical challenges highlighting the need to evaluate multi-level implementation processes to better understand and address inequities in GT completion. Participants suggested implementing early educational outreach, culturally relevant messaging, and interpersonal touchpoints to promote GT uptake. By applying a CBPR approach, we translated these findings into actionable, equity-focused strategies to improve GT completion within a population genetic screening program.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100591"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13071439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147475560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant selection to maximize variance explained in cis-Mendelian randomization.","authors":"Ang Zhou, Ville Karhunen, Haodong Tian, Janne Pott, Ashish Patel, Eric A W Slob, Stephen Burgess","doi":"10.1016/j.xhgg.2026.100573","DOIUrl":"10.1016/j.xhgg.2026.100573","url":null,"abstract":"<p><p>Optimal selection of instrumental variables (IVs) from a single gene region in cis-Mendelian randomization (MR) is challenging, as variants are highly correlated due to linkage disequilibrium (LD). Using only the lead variant is convenient but may not achieve full statistical power if multiple signals exist. We compared four selection methods that incorporate correlated non-lead variants, including LD-pruning, conditional and joint analysis (COJO), sum of single effects (SuSiE) regression, and principal component analysis (PCA), and evaluated their ability to increase instrument strength, measured by variance explained in the exposure (R²), relative to the lead-variant-only approach. We applied these methods to circulating haptoglobin (HP), to simulated traits with known variance explained, and to 15 additional gene regions where non-lead cis-protein quantitative trait loci (pQTLs) contributed varying proportions of cis-genetic variance. R² was estimated from variant-protein association estimates (Fenland study, n = 10,708) using LD from the UK Biobank (n = 356,557). In the HP region, the four methods produced a median proportional gain in R² of 145.1% compared with the lead variant alone (range: 69.6%-169.4%), with a median reduction in the MR standard error of 36.3% (range: -37.9% to -19.3%). In simulations, all methods were able to recover the expected genetic variance. Across the 15 gene regions, methods incorporating non-lead variants consistently outperformed the lead-variant-only approach. Variant selection methods incorporating correlated non-lead variants can reliably improve instrument strength in cis-MR analyses. We recommend using such methods but advise comparing their estimates with the lead-variant-only estimate to safeguard against numerical instability.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100573"},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12887808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}